We have established that neurons present in dorsal root ganglia (DRG), like leukocytes, express a wide variety of receptors for cytokines, chemokines, opioids, anandamide and neuropeptides. We previously showed that prior exposure to chemokines such as MIP1&#945; results in PKC mediated desensitization of the chemotactic response to opioids by opioid receptors, and thus potentially enhances pain. This decrease in the analgesic effect of opioids was evident from the enhanced tail flick assay of rats administered MIP1&#945; or RANTES prior to an analgesic opioid into the periaquaductal gray center (PAG) of the CNS. We then extended these earlier studies by showing that prior administration of chemokines sensitized and primed calcium flux induced by capsaicin or anandamide stimulated vanilloid (TRPV1) algesic receptor on DRG neurons. This response also increased pain as shown by the enhancement of paw withdrawal in response to the intrathecal administration of the chemokine prior to capsaicin in vivo. This sensitization of the vanilloid receptor was also PKC dependent. Consequently, proinflammatory chemokines can increase pain by suppressing opioid and enhancing vanilloid receptor responses. Based on these studies, we predicted that the anti-inflammatory effects of adenosine, which also interacts with GiPCR, might have effects on chemokine receptors. Indeed our current studies show that prior addition of adenosine results in suppressing the in vitro chemotactic response of leukocytes to a variety of chemokines. Furthermore, prior in vivo injection of adenosine inhibits the in vivo influx of leukocytes into a murine air pouch by about 90%. This cross-desensitization of chemokine receptors by adenosine A2a receptors was PKA dependent. These studies therefore reveal novel pathways of receptor mediated intercommunication of painful and inflammatory stimuli. Means of interfering with these PKC and PKA dependent signals and the pathophysiological relevance of this receptor cross-talk to inflammation and pain need to be further evaluated. We are currently investigating how these pathways may be contributing to the very painful inflammatory lesions of Herpes Zoster in animal models.